Diabetes remains a global epidemic afflicting more than 300 million people worldwide, with incidence only expected to rise. Despite decades of research the current standard of care for those suffering from type I diabetes (TID) remains a rigorous regimen of blood glucose monitoring together with daily administrations of exogenous insulin and diabetic diet, these individuals still are challenged with untoward side effects due to complications of the disease in part the result of daily compliance issues. Islet transplantation has tremendous potential, but serious technological limitations remain. The lack of suitable biomaterials used for cell encapsulation is one of the key obstacles to clinical application. Cell encapsulation materials used to date are immunogenic, and lead to tissue capsule formation and cell graft failure. To address this challenge, here we propose the synthesis of 7000 candidate immune modulatory alginate- based hydrogel capsule formulations for cell encapsulation and a high-throughput in vivo method for identification of novel materials which can enable long-term protection and viability of transplanted donor pancreatic islet cells. A first-generation screen of 774 alginate formulations guides our design of this proposed second generation 7000 analogue structures. To enable increased throughput of screening, we propose to implant mixtures of different materials in the same implantation site. To pair the material identity with the observed material function, we are developing a next-generation sequencing (NGS) assay to determine material identity via a single nucleotide polymorphism (SNP) genotype of co-encapsulated HuVEC cells. Preliminary results using a 84-plex SNP NGS panel on 23 volunteers indicate high confidence genomic identification using limited NGS reads. Thus, a typical implantation of 200 alginate beads (1.5mm diameter) allows the simultaneous evaluation of 20 different implanted materials, with still sufficient independent beads per material to allow statistical analysis. In the course of this research project, the PI will first synthesize the new analogue library compounds. Subsequently, the PI will screen these materials in vivo using a xenogeneic transplantation of islets/HuVEC mixtures into a profibrotic C57BL/6 model rodents, that enables us to simultaneously screen up to 20-fold more distinct materials formulations in a single rodent. Next, the PI will examine the ability of leads (5-10) formulations to protect transplanted islet and restore normoglycemia in a T1D rodent model for up to 100 days. Finally lead formulations will be further vetted in healthy non-human primate studies. We anticipate that upon completion of this project, lead alginate materials for encapsulating islet cells will be identified that succeed in two different animal models (C57BL/6 mouse and macaque monkeys) and will be ready for pre-clinical tests under GLP/GMP conditions in preparation for an FDA IND submission.